A pH/GSH dual-responsive Fe-based MOF drug carrier for ferroptosis-glycolysis synergistic therapy

Abstract

Ferroptosis, a recently recognized form of non-classical programmed cell death (PCD), leads to impaired cellular structure and integrity due to the accumulation of lipid peroxidation products (LPOs). However, single treatment ferroptosis often fails to achieve optimal tumor treatment outcomes. Therefore, we constructed a multi-synergistic treatment strategy based on ferroptosis that is more conducive to tumor therapy. In this study, we constructed a metal organic framework (MOF) loaded with glucose oxidase (GOx) and doxorubicin (DOX), denoted as Fe(III)-RSSR@DOX@PEG-GOx. Fe(III)-RSSR@DOX@PEG-GOx was synthesized through coordination between Fe³⁺ and disulfide-containing ligands, scavenged glutathione (GSH) and downregulated glutathione peroxidase 4 (GPX4), thereby triggering ferroptosis. The GOx catalyzes glucose into abundant H₂O₂, promoting the Fenton reaction, which results in excessive ROS formation within tumors. The accumulation of ROS can further enhance the process of ferroptosis, while the massive consumption of glucose constitutes a synergistic situation of “starvation treatment”. The smart biomimetic nanoplatform integrates ferroptosis, chemotherapy, and starvation therapy, providing a potential anti-tumor strategy for achieving multi-effect synergistic tumor treatment.